The story starts something like this: You wake up one morning and notice a new ache or pain that you didn’t have before. Once, you used to jump out of bed and hit the running machine or the weights; now, it can be a challenge to tie your shoelaces. The fight for longevity gets tougher every day. It gets worse: injuries that you used to quickly recover from are now taking far longer to heal, and you’re having trouble with moving and getting around like you used to.
The problem is that fighting with conventional methods has its limits. Exercise, a balanced diet, quality sleep, and other healthy practices will only get you so far; the outcome is ultimately still the same. Sooner or later, we all experience the ill health of old age; it is just a question of time. No one likes getting old, but that’s just the way it is, right?
That has certainly been true in the past, but things are happening now that could change how we think about and treat aging.
The last decade has seen somewhat of a revolution in the field of aging research; our understanding of what aging is has come a long way, as have the impressive array of tools and techniques that scientists now have at their disposal. Our knowledge about how aging works, what causes it, and what we might do about it has grown, yet this progress has gone largely unnoticed by the public.
What is aging?
Essentially, aging is damage and error, a collection of different processes that cause damage through the accumulation of waste, imperfect repairs, dysfunction and deregulation of cellular processes, and responses to these things.
In order to stay alive, the body attempts to maintain a balance between damage and repair, which is known as homeostasis. In simple terms, aging is what happens when that balance is lost and the body becomes damaged faster than it can repair itself. Eventually, the various aging processes result in the familiar signs of aging and the development of age-related diseases that finally kill us.
What can science do about it?
Research into developing solutions for reversing aging has recently revealed several solutions that have scientists optimistinc. We dive into the two principal ones.
In aging research, the burgeoning field of rejuvenation biotechnology is perhaps the most exciting. Rejuvenation biotechnology is a preventative approach to treating age-related diseases. It directly targets one or more of the aging processes to restore tissue and organ function to a more youthful state, thereby delaying, preventing, or even reversing age-related diseases.
Current medical care focuses on treating diseases as they appear, dealing with each new one as it develops. This approach works just fine with infectious diseases, but it’s an exercise in futility when age-related diseases are involved. It becomes a bit like playing a game of whack-a-mole; an age-related disease pops up and gets hammered down, only for more to pop up, and this cycle continues with an ever-falling hope of success and an ever-rising cost.
This is the polar opposite of the approach of rejuvenation biotechnology, which seeks to prevent these diseases from ever developing in the first place by directly targeting the aging processes that drive them.
Senolytics – Taking out the trash
One way in which rejuvenation biotechnology aims to achieve this is with senolytics, which are therapies that purge harmful senescent cells from the body.
As we age, our cells enter a state known as senescence: they no longer divide or support the tissues of which they are part. Normally, senescent cells destroy themselves via apoptosis, a kind of self-destruct mechanism, and are disposed of by the immune system. However, as we get older, more of these cells escape apoptosis; our immune systems also begin to wear out and stop removing them from our bodies.
This is a real problem because senescent cells secrete harmful chemical signals known as the senescence-associated secretory phenotype (SASP). This collection of pro-inflammatory signals causes the immune system to become dysfunctional and blocks tissue repair and function. If that was not bad enough, the SASP also encourages healthy neighboring cells to become senescent!
The accumulation of senescent cells has been implicated in a myriad of conditions, such as vascular aging, heart disease, type 2 diabetes, skin aging, osteoarthritis, Alzheimer’s, and cancer. It is also likely that many more age-related diseases are linked to the presence of senescent cells.
What is the solution?
In 2011, researchers set out to find out what would happen if senescent cells were cleared from the body. A team of Mayo Clinic researchers led by Jan van Deursen created a unique type of mouse that was engineered in such a way that, when exposed to a certain chemical, its senescent cells would destroy themselves.
The results of this experiment were stunning, to say the least. These two mice are littermates and the same age as each other. The mouse on the left is a control mouse that has aged normally, and the mouse on the right was given the compound that cleared the senescent cells from its body. The researchers discovered that, compared to their untreated littermates, mice treated with this senolytic therapy had some aspects of aging delayed.
A follow-up experiment in 2016 addressed some of the shortcomings of the previous experiment and really got things moving. Because the original experiment had used a special kind of mouse designed to react to a compound and whose senescent cells were not accumulated via natural aging, the experiment was not really representative of true aging. For validation, the approach needed to be demonstrated in normally aging mice.
The researchers used a drug that induced apoptosis in senescent cells; once again, they found that removing these cells improved the health of the mice and appeared to delay the aging of various organs and tissues. This experiment convinced researchers that the approach held great promise, and the race was on to develop therapies that could translate to humans.
There are now multiple companies developing senolytic therapies, and after raising $385 million in funding, UNITY Biotechnology is leading the way. The company’s first candidate drug, UBX0101, entered human trials in June 2018 and is focused on treating osteoarthritis, an age-related disease, and UNITY has a number of other age-related diseases in its pipeline.
If senolytics prove as successful in humans as they have in animals, they have the potential to be a real game changer.
Restoring metabolic balance with NAD+
In an attempt to hold off age-related diseases, researchers are also targeting the aging processes through a cellular therapy that improves metabolism and appears to delay aging.
Nicotinamide adenine dinucleotide (NAD+) is a major metabolic signaling molecule that is found in all living cells. NAD+ plays a key role in regulating metabolism by facilitating redox reactions and carrying electrons from one reaction to the next. NAD+ also facilitates DNA repair and many other important functions in the cell. Quite simply, without NAD+, life would be impossible.
The bad news is that as we age, the amount of NAD+ available in the cell falls significantly, leading to more and more dysfunction, a decline in DNA repair and energy production, and the loss of homeostasis, a form of metabolic balance. The age-related loss of NAD+ is implicated in a variety of metabolic disorders, including diabetes and vascular aging, and there is some data suggesting its involvement in heart disease.
We have known about NAD+ for over a hundred years; it was first discovered by Harden and Young in an experiment with yeast fermentation. NAD+ is created in two main ways: it is formed from the amino acid tryptophan and created by consuming food that contains nicotinic acid (niacin), nicotinamide riboside (NR), or nicotinamide mononucleotide (NMN), which are known as NAD+ precursors. However, it was not until recently that researchers started to consider NAD+ as a therapeutic target.
So, can we fix this by putting NAD+ into our bodies?
Due to the role of NAD+ in cellular function, metabolism, and aging, this has led some researchers to investigate if restoring NAD+ to a youthful level would improve metabolism and potentially prevent age-related diseases.
Unfortunately, it is not as simple as just introducing NAD+ directly into the bloodstream, as the molecule itself is rather large and cannot pass through the outer membranes of most cells. To get NAD+ into cells, it must first be delivered in the form of one of the precursor molecules, which are smaller and able to pass through these membranes.
Niacin is a NAD+ precursor with which you may already be familiar. It has long been used as a therapy for heart disease due to its effect on cholesterol. However, it is not very efficient at increasing NAD+ levels, as it has to go through many chemical changes before it becomes NAD+. Something better was needed.
Recent studies have shown that the precursor NMN added to the drinking water of aged mice was able to restore NAD+ levels to that of younger healthy mice within one week. There was considerable improvement of age-related metabolic dysfunction as well as improvement of muscle tissue. A further study suggests that metabolic disorders, such as type 2 diabetes, could be reversed by restoring NAD+ levels.
Finally, this year, a team led by Dr. David Sinclair at Harvard Medical School discovered that NAD+ also helped to restore blood flow in aged mice. Feeding NMN to old mice was shown to encourage the formation of new blood vessels supplying muscle tissue and other organs while improving the flow of blood, nutrients, and oxygen to the cells there. What was impressive was the 60% improvement of treadmill time that these treated mice showed compared to their untreated littermates of the same age. The old mice also doubled their exercise endurance, which became similar to or, in some cases, better than that of younger mice.
In a very real sense, NMN fools the body into thinking that it has been exercising, which leads to the same improvement of blood flow and endurance. Essentially, it could mean being able to create a pill that mimics the effects of running a ten-mile race every day without actually having to do it. This is particularly important for older people, who may not be able to exercise due to frailty or conditions preventing them from doing so; this goes beyond simply replacing the need to exercise and addresses important healthcare needs.
This also means that NMN could potentially not only improve circulation in the elderly, but it could also enhance circulation in athletes. Optimizing blood vessel growth and the flow of blood to muscles could boost performance, allow them to train longer and harder, and give them an important edge in races. Imagine being able to smash your personal best from your 20s in middle age!
Right now, the David Sinclair Lab at Harvard Medical School is conducting a human clinical trial at Brigham and Women’s Hospital; if successful, this should hopefully lead to larger studies and ultimately a therapy to help us stay healthier for longer.
Stem cells therapy to regenerate organs and tissue
Researchers are also trying to cure age-related diseases through something you may find familiar: stem cell therapy. Stem cell therapies have been around for well over a decade now, and they have seen considerable public exposure during that time.
All the cells in your body have the same genetic code, but depending on cell type and tissue, different areas of that code are turned off or on; this is called gene expression, and it allows each cell to specialize for the function that it is meant to perform. Normal cells are specialized and do not change their type or function very easily; however, stem cells are not so limited.
Stem cells have a greater amount of versatility, and the most basic stem cells can change their gene expression so that they can become any cell type in the body. This is very useful because it allows them to become the highly specialized cell types for our organs and, through division, repair and maintain organs and tissues.
Stem cells perform a wide range of functions, including beneficial signaling that improves tissue function as well as replacing lost or damaged red blood cells, white blood cells, and solid tissues.
When we are born, we are given pools of stem cells to last a lifetime; unfortunately, when they are gone, they are gone, and this is where the problem begins. As we grow older, we have fewer and fewer stem cells available to us, and while lost stem cells can be replaced through division, this happens less frequently as we age, and the stem cells become less active for a variety of reasons.
One reason is chronic age-related inflammation, the smoldering background of inflammatory signals that increases as we grow older and interferes with cell function and communication. This chronic inflammation, known as “inflammaging”, has a variety of sources, including the SASP from senescent cells, age-related changes to the bacteria in the gut, cell debris, and a dysfunctional immune system. Stem cells can also be lost by becoming damaged and entering senescence just like regular cells do, depleting our supplies further.
Stem cell depletion over the course of decades causes long-lived tissues, such as the brain, heart, and skeletal muscles, to gradually lose cells; this, in turn, compromises their function. Muscles begin to weaken, cannot recover from injury properly, and no longer respond to exercise, resulting in frailty and loss of mobility. In the brain, neurons are steadily lost, and without replacements, cognitive decline, dementia, and the loss of fine muscle control begin to set in.
The thymus, an immune organ that is located behind your breastbone and produces T cells to protect the body from infections, shrinks as the stem cell supply runs out, leaving us vulnerable to infectious diseases. Cartilage, the tough and flexible tissue that coats the surface of joints and enables bones to slide over each other while reducing friction, wears out and no longer acts as a shock absorber.
How can we fix this?
In the last decade or so, researchers have become increasingly skilled at creating replacement cells of the type needed for a specific organ or tissue in the body. To do this, they take normal adult cells from the patient and, using special chemicals, they “reprogram” the cells into an embryonic-stem-cell-like state. This causes the cells to forget their previous specialized roles and become flexible in the same way as naturally occurring stem cells so that they can become any other cell type in the body. These reprogrammed adult cells, known as induced pluripotent stem cells (iPSCs), can be guided to become other types of stem cells through various chemical prompts in order to replace lost stem cells in target organs and tissues.
A newer variation of this technique allows scientists to take normal cells of one type and change them directly to another type in the same tissue without the need to fully reprogram them back to an embryonic stem cell-like state. This technique is more efficient and faster, as it requires fewer steps than iPSC reprogramming. Normally, this new technique is done by taking the cells, modifying them outside the body in a dish, and reintroducing them; however, there has recently been progress within situ reprogramming, in which cells are changed from one type to another while still inside the body.
One of the most common focuses of stem cell therapies is for joint problems such as osteoarthritis and injury, and there have been considerable efforts to develop therapies to replace cartilage. However, using stem cells to encourage efficient regeneration currently remains elusive despite cartilage being fundamentally simple; unlike most other kinds of tissues, it only consists of a single cell type, the chondrocyte. Researchers can create chondrocytes via reprogramming, but their potential still remains limited, as the cartilage regenerated by these stem cells does not fully emulate the structure or biomechanical properties of naturally occurring cartilage.
However, research efforts are in progress, and, hopefully, these hurdles will be overcome in the near future, giving hope for restoring lost mobility and independence and even extending sporting careers. While pure stem cells are not yet available in the U.S. outside of clinical studies, these studies have shown some promising early results, and as progress in the stem cell field has been rapid in recent years, there is plenty of reason to be positive about the future.
What can we do now?
Right now, scientific evidence shows that the three best things that you can currently do to maximize your chances of living longer and staying healthy involve diet, exercise, and sleep.
Eating a good diet improves your metabolism, which can slow down the effects of aging. It helps to control the activity of insulin and insulin-like growth factor 1 (IGF-1), which both have a strong influence on how quickly we age.
When you eat something, it causes glucose to enter the bloodstream; this peaking glucose increases insulin, which allows the glucose to enter your cells so that it can be consumed. The presence of insulin also encourages the production of IGF-1. However, excessive insulin and IGF-1 can increase the risk of cancer and raise all-cause mortality risk. High insulin levels also harm the sensitivity of our insulin receptors, preventing our cells from responding to the presence of nutrients properly, which increases the risk of developing metabolic conditions such as type 2 diabetes.
When glucose peaks are both high and regular, they lead to insulin resistance and can cause increased blood pressure, a risk factor in the development of heart and kidney disease. Studies have shown that animals with low or artificially suppressed levels of IGF-1 live longer, and as we share the same insulin and IGF-1 mechanisms, it is reasonable to assume that keeping insulin and IGF-1 levels low and avoiding regular peaks (having a low glycemic load) may also be beneficial to us.
Keeping your levels low and steady is somewhat challenging but doable if you are committed to staying healthy for longer. In general, avoiding simple carbs is the key to keeping your diet at a low glycemic load. Cakes, bread, sugar, candy, fruit juice, pasta, and rice are all bad news for your glycemic load, and care should be taken to avoid them, as they all cause blood glucose to increase and result in insulin and IGF-1 increases and spikes. Also, avoid trans fats, red meat, and fried food in general.
A diet rich in plant matter and fiber is good, but you should avoid cooking vegetables, as cooking raises their glycemic index; potatoes and root vegetables are particularly bad in this respect. Fiber is great to include in the diet, as the beneficial bacteria in our guts feed on it and produce the short chain fatty acid butyrate, which is linked to energy metabolism, gut wall integrity, and the regulation of inflammation. There is a growing amount of evidence that changes to the gut bacteria that result in the loss of butyrate production contribute to inflammaging, the constant background of low-grade inflammation. Inflammaging is also a strong predictor of the decline of health and fitness in older people.
Next to diet, exercise is probably the best measure you can take against aging. Aim to perform at least 30 minutes of physical activity a day. Walking, cycling, dancing, and swimming are ideal activities, as they are low impact and kinder on joints; this is especially important as you approach middle age and beyond, as injuries become more commonplace and healing becomes harder. Walking has been shown to reduce mortality in older people.
Another study showed that both dancing and fitness training can induce hippocampal plasticity in the elderly, but only dancing improved balance capabilities. Even light activity has a noticeable effect on mortality and includes things such as housework. Scientific literature is filled with examples of how exercise positively impacts aging and presents a solid case for doing it regularly.
Finally, adequate sleep is also essential for health and longevity. Our circadian rhythms are known to change with age and become increasingly disrupted as we grow older, making high-quality sleep and its restorative effects increasingly elusive. To try to reduce the impact that aging has, try to ensure that you get plenty of restful sleep. Eliminate sources of light that can make it harder to get to sleep; for example, you may wish to invest in heavy curtains to block out light coming from outside. Avoid going to bed with your phone, and try to have a relaxing hour before bed during which you read a book and avoid overly stimulating activity, such as video gaming and watching films. You should aim to sleep for 7-8 hours a day if possible.
Stay healthy and active
The field of rejuvenation biotechnology is an exciting and rapidly progressing scientific field with the potential to change how we regard and treat age-related diseases forever. We have almost certainly only just taken our first steps on the road towards what might be possible, but there are already signs of exciting things ahead. Meanwhile, the best thing we can all do right now is to stay healthy and active as long as possible and hopefully live long enough to see these and other therapies arrive.
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